Corticosteroid containing orally disintegrating tablet compositions for eosinophilic esophagitis

ABSTRACT

The present invention is directed to orally administered compositions of topically acting corticosteroids for the treatment of inflammation of the gastrointestinal tracts such as eosinophilic esophagitis. The present invention also provides a method for treating conditions associated with inflammation of the gastrointestinal tract in an individual. The method comprises administering to an individual in need thereof a pharmaceutical composition of the present invention as orally disintegrating tablets comprising a topically active corticosteroid adsorbed onto a pharmaceutically acceptable carrier such as silicified microcrystalline cellulose.

CROSS-RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.16/578,568, filed Sep. 23, 2019, which is a Divisional of U.S. patentapplication Ser. No. 14/917,125, filed Mar. 7, 2016, which is the U.S.National Stage of International Patent Application No.PCT/US2014/054203, filed Sep. 5, 2014, which claims the benefit ofpriority under 35 USC § 119(e) of U.S. Provisional Patent ApplicationNo. 61/874,450, filed Sep. 6, 2013, disclosures of which are hereinincorporated by reference in their entireties for all purposes.

FIELD OF THE INVENTION

This invention relates to orally administered low dose, topically actingcorticosteroid compositions, useful for the treatment of conditionsassociated with inflammation of the esophagus.

BACKGROUND OF THE INVENTION

Esophageal inflammation disorders such as eosinophilic esophagitis (EoE)characterized by high levels of eosinophils in the esophagus, as well asbasal zonal hyperplasia, are gaining increased recognition in childrenand adults. Many aspects of the disease remain unclear including itsetiology, natural history, and optimal therapy. EoE affects all agegroups but most frequently individuals between 20 and 50 years of age.Symptoms of EoE often mimic those of gastroesophageal reflux disease(GERD) and include vomiting, dysphagia, pain and food impaction. Thecommon occurrence regarding misdiagnosis of EoE for GERD often resultsin delayed treatment in patients with EoE. There are currently noapproved topically administered anti-inflammatory medications for thetreatment of conditions associated with inflammation of the upperportion of the gastrointestinal tract, particularly the inflammatoryconditions of the esophagus, i.e., EoE. The disease is painful, leads todifficulty swallowing and predisposes patients to food impaction andother complications. Although systemic treatments with corticosteroidssuch as prednisolone are effective, they are associated with significantadverse effects such as suppression of the hypothalamo-pituitary-adrenal(HPA) axis as reflected in salivary cortisol levels, generalizedsuppression of immune function, and particularly in children, troublingside-effects from long term systemic exposure include growthretardation, which may lead to a reduction in adult height.

In contrast, twice-daily treatments of EoE include directing steroidmedications through a metered dose inhaler (MDI) to the back of thethroat such that they are not appreciably inhaled, and instructing thepatient to keep the mouth closed during the “puff and swallow” treatmentand rinse the mouth immediately after administration, and not to swallowfood or water for two hours after administration. Rinsing is recommendedbecause residual drug in the mouth and throat can lead to candidiasisinfection, and swallowing is contraindicated because it may wash drugaway from the esophagus. In another study, 50% of fluticasone propionate(FP)-treated patients achieved histologic remission compared with 9% ofpatients receiving placebo (P=0.047), FP decreased esophageal eosinophillevels, with a more pronounced effect in non-allergic individuals.However, this therapy is particularly problematic for younger childrenand those with developmental delay, who are unlikely to utilize thispuff and swallow technique effectively.

In another randomized, double blind, placebo controlled trial performedto evaluate the effect of oral 1 mg budesonide viscous solution (0.5-mgrespule dissolved along with five 1-g packets of sucralose in 10-15 mLfluid) dosed twice daily vs. placebo in adolescent and adult patientswith active EoE for 15 days, the pretreatment and post treatment diseaseactivities were assessed clinically, endoscopically, and histologically.The primary end point was reduced mean numbers of eosinophils in theesophageal epithelium (number per high-power field [hpf]=esophagealeosinophil load). A 15-day course of treatment with budesonide is welltolerated and highly effective in inducing a histologic and clinicalremission in adolescent and adult patients with active EoE. A 15-daycourse of therapy significantly decreased the number of eosinophils inthe esophageal epithelium in patients given budesonide (from 68.2 to 5.5eosinophils/hpf; P<0.0001); but not in the placebo group (from 62.3 to56.5 eosinophils/hpf; P=0.48). Dysphagia scores significantly improvedamong patients given budesonide compared with those given placebo (5.61vs 2.22; P<0.0001). White exudates and red furrows were reversed inpatients given budesonide, based on endoscopy examination. This dosageform has not been FDA approved for commercial use, and the oraladministration is going to be messy and likely to produce inconsistentresults.

When oral solid dosage forms with a drug load of ≤5% by weight arerequired, the drug is either micronized and co-processed by blendingwith at least one carrier excipient or granulating in a fluid bed orhigh shear granulator by spraying preferably a solution of the drug toachieve blend uniformity/homogeneity of the blend and subsequently,content uniformity in the finished dosage units per regulatoryrequirements (FDA's Draft Guidance for Industry “Powder blend andfinished dosage units—stratified in-process dosage unit sampling andassessment” October 2003). Many micronized drugs show a tendency tosegregate and form larger particles in the blend in order to reducetheir high surface energy, resultant segregation and agglomeration couldcause resurfacing of the blend non-uniformity/inhomogeneity issues setout to resolve in the first place. Segregation and agglomeration in theblends containing especially poorly water soluble, low-dose drugs mustbe avoided not only during powder blending but also until processed intofinished dosage forms, capsules or tablets, to achieve and maintaindesired blend uniformity/homogeneity and/or to avoid high dissolutionvariability. Segregation of drug particles, especially in directcompression blends, is equipment and material dependent. It is thus verychallenging to achieve acceptable blend homogeneity during directcompression blending of a low-dose drug with suitable pharmaceuticallyacceptable excipients (i.e., at a drug content of <5% by weight in theblend) and maintain the blend homogeneity until processing into finisheddosage forms (e.g., tablets or capsules) (McGinity J. W. et al.Dissolution and uniformity properties of ordered mixes of micronizedgriseofulvin and a directly compressible excipient Drug Development andIndustrial Pharmacy 1985; 11(4): 891-900; Yalkowsky S. H. and Bolton S.Particle size and content uniformity, Pharmaceutical Research, 1990;7(9): 962-966; Ahmad H. and Shah N. Formulation of low dosemedicines-Theory and Practice, Amer. Pharm. Rev. 2000; 3 (3): 1-5;Mahmoudi Z. N. et al. The influence of filler in blend uniformity ofmicronized drugs. Contributed poster, AAPS Annual Meeting (USA) 2010;Mahmoudi Z. N. et al. Effect of drug particle size on blend segregationand content uniformity. Contributed poster, AAPS Annual Meeting (USA)2011).

WO2011041509 discloses the preparation of an orally administrablepharmaceutical composition containing a topically acting corticosteroidin an amount of less than 20 mg. Although there is no specificdiscussion of how to achieve acceptable blend uniformity in the workingexample of the compression blend which contains fluticasone propionateat only 4% by weight, which will be translated into achieving acceptablecontent uniformity of the ODTs, the fact that fluticasone is granulatedwith suitable pregranulated excipients, such as rapidly dispersingmicrogranules comprising mannitol and crospovidone, suggests that thegranulation of fluticasone has been performed for the purpose ofachieving acceptable content uniformity in the finished tablets.However, the micronized topically acting corticosteroid particles may bepresent in the agglomerated granules and as such may not be readilyexposed to the inflamed EoE tissues upon oral administration for rapidinduction of remission of EoE.

There is therefore a need for low-dose corticosteroid compositionshaving acceptable blend uniformity/homogeneity during blending of atopically acting corticosteroid with suitable pharmaceuticallyacceptable excipients as a carrier (i.e., at a drug content of <5%,especially at <3% by weight in the blend) and maintain the blendhomogeneity until processing into finished unit dosage forms (e.g.,tablets or capsules), which while exhibiting high content uniformity aresuitable for oral administration in patients to provide topical (ratherthan systemic) treatment of inflammation of the of the uppergastrointestinal tract, particularly eosinophilic esophagitis (EoE)since the micronized, topically acting corticosteroid particles havingbeen adsorbed largely on the surface of the carrier are capable ofrapidly inducing remission of EoE.

SUMMARY OF THE INVENTION

The present invention is directed to an oral solid pharmaceuticalcomposition comprising a low-dose topically acting corticosteroid and atleast one pharmaceutically acceptable carrier for adsorption of thedrug, wherein the drug is in an amount of less than about 5% (weight ofdrug/weight of composition), particularly less than 3% by weight and thecomposition has no significant systemic glucocorticoid ormineralocorticoid activity after oral administration in humans. Theblend of a corticosteroid with the carrier has high blenduniformity/drug homogeneity which is translated into content uniformityof finished unit tablets.

The composition of the invention which can be formulated as an orallydisintegrating tablet (hereafter referred to as an ODT) thatdisintegrates within 30 seconds when tested using the USP <701>Disintegration Test, and/or disintegrates within 60 seconds when placedin the oral cavity of a human.

The present invention is also directed to a process for making low dosepharmaceutical compositions comprising adsorbing a topically actingcorticosteroid optionally micronized onto at least one pharmaceuticallyacceptable carrier such as silicified microcrystalline cellulose byblending for a sufficiently long time and passing through ade-segregating/comminuting mill at least once before blending with otherpharmaceutically acceptable excipients, and then formulating theresulting blend into a suitable unit dose presentation, e.g., tableting.

The present invention discloses a method of preparing pharmaceuticalcompositions comprising especially poorly water soluble, low-dose,micronized drugs and at least one pharmaceutically acceptable carrierwhich must be blended for a sufficiently long time using a suitableblender-comminuting mill combination, thereby avoidingsegregation-agglomeration of the drug particles in the blend not onlyduring powder blending but also until processed into finished dosageforms, capsules or tablets, to achieve and maintain desired high blenduniformity/homogeneity and/or to achieve high content uniformity of thefinished dosage units and also to avoid high dissolution variability.

The compositions of the present invention are useful for treatment ofvarious conditions including the inflammatory conditions of thegastrointestinal tract. Accordingly, the present invention also providesa method for treating inflammatory conditions of the uppergastrointestinal tract in an individual particularly in the esophagus(eosinophilic esophagitis) via topical action with minimal systemicabsorption and concomitant corticosteroid related side-effects. Themethod comprises administering to an individual to treat eosinophilicesophagitis a pharmaceutical composition of the present inventioncomprising topically acting optionally micronized corticosteroidparticles adsorbed onto silicified microcrystalline cellulose.Alternatively, the compositions of the present invention may comprise awater soluble or water-swellable pharmaceutically acceptable excipient,such as bio-gelling or bioadhesive polymer that will enhancebioadherence of the corticosteroid to the inflammed esophageal mucosa.

DETAILED DESCRIPTION OF THE FIGURES

FIG. 1 shows the sampling locations in a blender for takingrepresentative samples as per draft FDA Guidance (FDA's Draft Guidancefor Industry “Powder blend and finished dosage units—stratifiedin-process dosage unit sampling and assessment” October 2003).

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a solid pharmaceutical composition whichcomprises a corticosteroid in an amount of less than about 5% (weight ofdrug/weight of composition) and at least one pharmaceutically acceptablecarrier for adsorption of the drug, wherein the composition has nosignificant systemic glucocorticoid or mineralocorticoid activity, andwherein the solid pharmaceutical composition disintegrates within 30seconds when tested using the USP <701> disintegration method. Thecomposition disintegrates in about 60 seconds or less on contact withsaliva in the oral cavity of a subject or patient in need thereof.

The solid pharmaceutical composition of the present invention provides atherapeutically effective amount of a topical corticosteroid to inflamedtissues of the upper gastrointestinal tract, particularly to theesophageal inflamed tissues.

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall have the followingmeanings.

The term “drug”, “active” or “active pharmaceutical ingredient” as usedherein includes a pharmaceutically acceptable and topically actingcorticosteroid, pharmaceutically acceptable salts, esters, solvates(including hydrates), polymorphs, stereoisomers, and/or prodrugs, andmixtures thereof. The terms “salts” refers to the product formed by thereaction of a suitable inorganic or organic acid with the “free base”form of the drug. Suitable acids include those having sufficient acidityto form a stable salt, for example acids with low toxicity such as thesalt approved for use in humans or animals. Non-limiting examples ofacids that may be used to form salts of a orally active drug, includeinorganic acids, e.g., HCl, H₃PO₄H₂SO₄. Non-limiting examples of organicacids include alkyl sulfonic acids and propionic acid.

The terms “orally disintegrating tablet”, “orally dispersing tablet”, or“ODT” refer to a solid dosage form of the present invention, whichdisintegrates rapidly in the oral cavity of a patient afteradministration, without chewing. The rate of oral disintegration canvary, but is significantly faster than the rate of oral disintegrationof conventional solid dosage forms or chewable solid dosage forms (i.e.,tablets or capsules) which are intended to be swallowed immediatelyafter administration.

The term “about”, as used herein to refer to a numerical quantity,includes “exactly”. For example, “about 30 seconds” includes 30 seconds,exactly, as well as values close to 30 seconds (e.g., 25 seconds, 29seconds, 31 seconds, 35 seconds, etc.). When the term “about” is used inreference to a range of values, the term “about” refers to both theminimum and maximum value of the range (e.g., “about 1-50 μm” means“about 1 μm to about 50 μm”).

The term “intimately associated”, as used herein to describe the spatialrelationship between two or more components of a composition refers tocomponents that are intimately mixed, such as, for example, in mixtures,coatings and matrices.

Unless indicated otherwise, all percentages and ratios are calculated byweight. Unless indicated otherwise, all percentages and ratios arecalculated based on the total composition.

The term “having no significant systemic glucocorticoid ormineralocorticoid activity”, as used herein refers to corticosteroidcompositions which do not provide a generalized effect in the bodythrough absorption into the circulation, but do provide local effectsthrough topical contact with a diseased tissue. Corticosteroids whichhave high systemic glucocorticoid potencies when administered orallyinclude e.g., hydrocortisone, prednisone, prednisolone,methylprednisolone, dexamethasone, betamethasone, etc. ormineralocorticoid potencies (e.g., alsosterone). Corticosteroids whichtypically have systemic glucocorticoid or mineralocorticoid activitywhen administered orally can also be used in the diluted compositions ofthe present invention, wherein the systemic uptake of the corticosteroidis reduced or suppressed.

Suitable topically acting corticosteroids which may be included in thepharmaceutical composition of the present invention include budesonide,fluticasone, flunisolide, ciclesonide, mometasone, beclomethasone,tixocortol and salts, or esters and mixtures thereof.

In a particular embodiment, the composition of the present inventioncomprises fluticasone. In other embodiments, the composition of thepresent invention comprises budesonide. In certain other embodiments,the composition of the present invention comprises ciclesonide.

In one embodiment, the corticosteroid may be in the form of crystalshaving a mean particle size of about 100 μm or less, about 75 μm orless, about 50 μm or less, more particularly about 25 μm or less, orabout 15 μm or less. A particular embodiment of the invention is wherethe corticosteroid is micronized in order to achieve a mean particlesize of less than about 10 μm, less than about 8 μm or less, less thanabout 6 μm, or particularly, less than about 4 μm. Alternatively, suchcrystals may have an average size in the sub-micron range (e.g., averageparticle size of about <1 μm), i.e., may be as nanoparticles (e.g.,average particle size in the range of about 1-100 nm).

In another embodiment, the corticosteroid may be present in an amorphousform, for example in association with a stabilizing agent which limitsdrug recrystallization, e.g., polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose, hydroxyethycellulose;SOLUPLUS®, KOLLIDON® VA64, sodium lauryl sulphate, Tween surfactants,EUDRAGIT® EPO polymer, and mixtures thereof.

The amount of corticosteroid present in the pharmaceutical compositionsof the present invention is selected so as to maximize the therapeuticbenefit from topical administration while minimizing side effects fromsystemic absorption. In the case of solid pharmaceutical compositions ofthe present invention, the amount of corticosteroid in the compositionis less than about 5% w/w (weight of drug/weight of composition). In oneembodiment the amount of corticosteroid in the pharmaceuticalcomposition is less than about 4%. In another embodiment it is less thanabout 3%. In yet another embodiment it is less than about 2%, less thanabout 1.5%, less than about 1%, less than about 0.5% by weight or less.In one embodiment the amount of corticosteroid in the pharmaceuticalcomposition is between about 0.50 mg and about 18 mg. In still anotherembodiment the amount of corticosteroid in the pharmaceuticalcomposition is between about 0.75 mg and about 12 mg. In yet anotherembodiment the amount of corticosteroid in the pharmaceuticalcomposition is between about 1.5 mg and about 9 mg. In still otherembodiments, the amount of corticosteroid is about 0.01 mg, about 0.05mg, about 0.1 mg, about 0.15 mg, about 0.1 mg, about 0.2 mg, about 0.25mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5mg, about 0.6 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 1 mg,about 1.5 mg, about 2 mg, about 3 mg, about 4 mg, about 4.5 mg, about 5mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about12 mg, about 18 mg, inclusive of all ranges and sub-ranges therebetween.

In the embodiment of the invention the rapidly disintegratingcomposition of the invention may comprise pharmaceutically acceptableexcipients which swell, dissolve or otherwise facilitate disintegrationof the ODT composition forming a smooth viscous suspension containingmicronized corticosteroid particles to coat inflammatory esophagealmucosa to treat eosinophilic esophagitis. In certain embodiments of thepresent invention the total weight of the dosage form is kept in therange of from 300 to 900 mg to incorporate as much rapidly dispersingmicrogranules comprising at least one sugar alcohol in combination withat least one disintegrant, as possible to maximize eosinophilicesophagitis surface coating with micronized corticosteroid. In anotherembodiment, the rapidly dispersing microgranules comprise at least onedisintegrant in combination with a sugar alcohol and/or a saccharide.The amount of sugar alcohol and/or saccharide in the rapidly dispersinggranules ranges from about 99%-90%, or about 95%-90% of the total weightof the disintegrant-containing granules, including all ranges andsub-ranges there between. In one embodiment, the average particle sizeof a sugar alcohol and/or saccharide is about 30 μm or less, for exampleabout 1-30 μm, about 5-30 μm, about 5-25 μm, about 5-20 μm, about 5-15μm, about 5-10 μm, about 10-30 μm, about 10-25 μm, about 10-20 μm, about10-15 μm, about 15-30 μm, about 15-25 μm, about 15-20 μm, about 20-30μm, about 20-25 μm, or about 25-30 μm.

In one embodiment of the invention the dosage form has total weight of300 mg and contain about 0.05 mg (0.16%), about 0.75 mg (0.25% w/w),about 1.5 mg (0.5% w/w), about 3 mg (1% w/w), about 4.5 mg (1.5%), about6 mg (2% w/w), about 9 mg (3% w/w), about 12 mg (4% w/w), about 16 mg(5%) of the corticosteroid.

In another embodiment of the invention the dosage forms has total weightof 600 mg and contain about 0.75 mg (0.125% w/w), about 1.5 mg (0.25%w/w), about 3 mg (0.5% w/w), about 4.5 mg (0.75%), about 6 mg (0.1%w/w), about 9 mg (1.5% w/w), about 12 mg (2% w/w), about 18 mg (3% w/w)of the corticosteroid. In one embodiment of the invention the topicallyacting corticosteroid is fluticasone propionate and it is in the rangeof about 0.05 to about 15 mg in the pharmaceutical composition at a drugcontent of from about 0.16% to 5% by weight of the composition.

In another embodiment the fluticasone propionate is in the range ofabout 0.75 to about 4.5 mg in the composition at a drug content of fromabout 0.25% to 1.5% by weight in the composition.

In another embodiment the fluticasone propionate is in the range of 0.05to about 18 mg in the composition at a drug content of from about 0.125%to 5% by weight in the composition.

The pharmaceutically acceptable carrier used in the mixture of thepresent invention is suitable for adsorption of the drug, it should havethe properties of an excellent carrier for dry blends providing blendflowability and workability and preventing the segregation. It mayconcur in providing corticosteroid content uniformity. It is selectedfrom the group consisting of microcrystalline cellulose, silicifiedmicrocrystalline cellulose, pregelatinized starch, corn starch,colloidal silica, or amorphous magnesium aluminum silicate (commerciallyavailable as VEEGUM™ or NEUSILIN™). It is preferably silicifiedmicrocrystalline cellulose which is composed of intimately associatedmicrocrystalline cellulose and colloidal silicon dioxide particles,(PROSOLV® SMCC; MCC, 98% and CSD, 2%). The use of this ingredient in thecomposition of the invention improves the flow and blending propertiesof the corticosteroid mixture; improved blend uniformity/homogeneity andphysical stability of the formulations during storage until their finalprocessing into finished dosage forms such as tablets or capsules, i.e.,to avoid or minimize potential de-mixing and segregation ofcorticosteroid microparticles is also achieved. The presence of thiscarrier in admixture with the active also ensures reproducibility ofpreparations of the composition of the invention (in particular with theapplied technology of direct tableting). In one embodiment of thepresent invention a low dose corticosteroid blend with the carriershowing high blend uniformity, low segregation potential and excellentflowability is disclosed. This blend is particularly suitable forproducing a rapidly disintegrating diluted corticosteroid composition.In one embodiment of the invention the blend comprises fluticasonepropionate adsorbed on silicified microcrystalline cellulose, andrapidly dispersing microgranules.

The rate of disintegration of the compositions of the present inventionin the oral cavity of an individual can be on the order of about 60seconds or less, about 50 seconds or less, about 40 seconds or less,about 30 seconds or less, about 20 seconds or less, or about 10 secondsor less.

The rate of disintegration of the solid pharmaceutical compositions ofthe present invention measured using the USP <701> Disintegration Testis about 60 seconds or less, about 45 seconds or less, about 30 secondsor less, about 20 seconds or less, or about 10 seconds or less.

In addition to the corticosteroid and the carrier, the blend of thecompositions or the oral dosage forms of the present invention maycontain further pharmaceutically acceptable ingredients which swell,dissolve or otherwise facilitate disintegration. Such ingredients caninclude disintegrant, a sugar alcohol, a saccharide, or a mixturethereof, a water-soluble polymeric binder, a bio-gelling or abioadhesive polymer, which can retain the corticosteroid particleadhered onto the inflamed esophageal tissues longer than in its absence.

In one embodiment, the present invention provides a solid pharmaceuticalcomposition comprising a corticosteroid and a pharmaceuticallyacceptable bio-gelling polymer which enables longer retention of thecorticosteroid at the inflamed esophageal tissues. The ingredient hereincalled “bio-gelling polymer” or “bio-adhesive agent” is an agent whichpromote adhesion of the corticosteroid to biological surfaces,especially the inflamed mucosa through gelling under GI tractphysiological conditions, for example, upon contact with physiologicalfluids and/or at physiological temperature, and includes, but is notlimited to the bin-gelling polymers listed below.

The bio-gelling polymer may be a thermosensitive polymer. Suitablethermosensitive polymers include polyacrylamides, such aspoly(N-isopropylacrylamide), as well as poly(ether-ester) copolymers,such as poly(ethylene glycol-(DL-lactic acid-co-glycolic acid)-ethyleneglycol). Such thermosensitive polymers can partially or fully cover theinflamed esophageal tissues while keeping the corticosteroid particle(s)close or in intimate contact with the inflamed tissues, therebyincreasing the topical contact of the corticosteroid with the inflamedtissues.

In one embodiment, the composition of the present invention includes abioadhesive agent such as a lipid or a polymer. Examples of such lipidsare glycerphospholipids such as phosphatidyl choline, and diacylglycerols such as glycerol dioleate. Examples of bioadhesive polymersinclude chitosan, polyorthoesters, and copolymers, terpolymers andmixtures thereof.

In another embodiment, the solid pharmaceutical compositions of thepresent invention include an adhesive agent. Suitable adhesive agentsinclude sucrose aluminum sulfate complex, chitosan and derivatives suchas trimethylchitosan, polyvinylpyrrolidone, methylcellulose,hydroxypropyl cellulose, cross-linked polyacrylic acid copolymers,polyvinylpyrrolidone, vinylpyrrolidone-polyvinyl acetate copolymer(e.g., KOLLIDON® VA 64 from BASF), SOLUPLUS®, poly(ethylene glycol6000-vinylcaprolactam-vinyl acetate) (13:57:30) copolymer from BASF),polyvinyl alcohol, polyethylene oxide, polyamide, alginic acid and itssalts, carrageenan, xanthan gum, ammoniomethacrylate copolymers,CARBOPOL polymers, maltodextrins, pectins, sucralose, and combinationsthereof.

In certain embodiments of the solid pharmaceutical compositions of thepresent invention, the corticosteroid and the adhesive agent areintimately associated. In one such embodiment the solid pharmaceuticalcomposition comprises corticosteroid surrounded or encapsulated by theadhesive agent. In another such embodiment the solid pharmaceuticalcomposition comprises corticosteroid disposed on the surface of theadhesive agent. In still other embodiments, the solid pharmaceuticalcomposition comprises corticosteroid mixed or granulated with theadhesive agent.

In certain embodiments of the present invention, the solidpharmaceutical composition includes any solid dosage form whichdisintegrates rapidly in the mouth to form a suspension of powderedcorticosteroid, which is hypothesized to coat or adhere onto theinflamed esophageal mucosa when swallowed.

In one embodiment, the composition of the present invention is in theform of an ODT. The ODT comprises the drug is in amount less than about5% (weight of drug/weight of composition) and a pharmaceuticallyacceptable carrier, wherein the composition has no significant systemicglucocorticoid or mineralocorticoid activity after oral administrationin humans. The drug particles, (e.g., a corticosteroid as describedherein optionally coated or optionally combined with an adhesive agentas described herein) are combined with rapidly dispersing microgranules.Rapidly dispersing microgranules comprise a sugar alcohol, a saccharide,or a mixture thereof and a disintegrant alone or a disintegrant incombination with a pharmaceutically acceptable additive withmulti-functional activity (e.g., pregelatinized starch,hydroxypropylcellulose or the like).

A non-limiting list of suitable disintegrants for the rapidly dispersingmicrogranules includes crospovidone (cross-linked PVP), sodium starchglycolate, cross-linked sodium carboxymethylcellulose, calcium silicate,and low substituted hydroxypropyl cellulose.

The amount of disintegrant in the ODT is typically in the range of about1% to about 10% by weight.

Sugar alcohols are hydrogenated forms of carbohydrates in which thecarbonyl group (i.e., aldehyde or ketone) has been reduced to a primaryor secondary hydroxyl group. Non-limiting examples of suitable sugaralcohols for the rapidly dispersing granules of the pharmaceuticalcompositions of the present invention include e.g., arabitol, isomalt,erythritol, glycerol lactitol, mannitol, sorbitol, xylitol, maltitol,and mixtures thereof. The term “saccharide” is synonymous with the term“sugars” includes monosaccharides such as glucose, fructose, thelactose, and ribose and disaccharides such as sucrose, lactose, maltose,trehalose, and cellobiose. In one embodiment, non-limiting examples ofsuitable saccharides for use in the compositions of the presentinvention include e.g., lactose, sucrose, maltose, and mixtures thereof.In another embodiment, the rapidly dispersing granules comprise at leastone disintegrant in combination with a sugar alcohol. In anotherembodiment, the rapidly dispersing granules comprise at least onedisintegrant in combination with a saccharide. In yet anotherembodiment, the disintegrant-containing granules comprise at least onedisintegrant in combination with a sugar alcohol and a saccharide.

The amount of sugar alcohol and/or saccharide in the rapidly dispersinggranules ranges from about 99%-90%, or about 95%-90% of the total weightof the disintegrant-containing granules, including all ranges andsub-ranges there between.

The amount of sugar alcohol and/or saccharide in the ODT ranges fromabout 30% to about 70% by weight.

In one embodiment, the average particle size of a sugar alcohol and/orsaccharide is 30 μm or less, for example about 1-30 μm, about 5-30 μm,about 5-25 μm, about 5-20 μm, about 5-15 μm, about 5-10 μm, about 10-30μm, about 10-25 μm, about 10-20 μm, about 10-15 μm, about 15-30 μm,about 15-25 μm, about 15-20 μm, about 20-30 μm, about 20-25 μm, or about25-30 μm.

The ratio of the disintegrant to the sugar alcohol, saccharide, ormixture thereof in the rapidly dispersing microgranules ranges fromabout 90/10 to about 99/01, for example about 90/10, about 91/9, about92/8, about 93/7, about 94/6, about 95/5, about 96/4, about 97/3, about98/2, about 99/1, inclusive of all values, ranges, and sub-ranges therebetween.

The corticosteroid particles are typically adsorbed onto the carrier.The process for the preparation includes repeatedly mixingcorticosteroid and carrier so that the blend is adsorbed onto thecarrier. Corticosteroid is typically micronized (mean particle size ofless than 10 μm) for the following reasons. Firstly, the finished dosageform (such as the ODT) is designed to rapidly disintegrate on contactwith saliva in the oral cavity. In order to accomplish this, the dosageform (ODT) should have preferably a minimum of 100 mg of rapidlydispersing microgranules, irrespective of the dose of corticosteroid(for example, 0.1 mg, 1 mg, 10 mg or 20 mg). Secondly, in order toachieve blend uniformity/homogeneity in the blend and content uniformityof the finished unit dosage forms, a homogeneous distribution could beachieved by incorporating the micronized drug particles in silicifiedmicrocrystalline cellulose alone or in combination with rapidlydispersing microgranules by at least once blending and milling asdescribed in examples of different embodiments of the present invention.The first option of incorporating the drug in the silicifiedmicrocrystalline cellulose will largely prevent segregation ofcorticosteroid microparticles during transient storage until finalprocessing into finished dosage forms, capsules or tablets exhibitinghigh content uniformity and/or low dissolution variability.

Rapidly dispersing granules or granulate can be prepared as described inU.S. 2005/0232988 or U.S. 2003/0215500 by granulating a disintegrantwith a sugar alcohol and/or saccharide having an average particle sizeof not more than about 30 μm. The granulation can be carried out, forexample, in a high shear granulator with approximately 20-25% water asthe granulating fluid, and if needed wet milled and dried to producerapidly dispersing microgranules having an average particle size of notmore than about 300 μm (e.g., about 175-300 μm). Rapidly dispersingmicrogranules can alternatively be prepared as described in U.S. Ser.No. 13/310,632 by granulating a sugar alcohol, a saccharide, or amixture thereof and a disintegrant in combination with apharmaceutically acceptable additive with multi-functional activity(e.g., starch, hydroxypropylcellulose or the like) at a low level of0.5-3.0% by weight in a fluid bed granulator.

The rapidly dispersing microgranules present in the ODT help rapiddisintegration of the tablet when placed in the oral cavity, creating asmooth suspension containing the corticosteroid drug particles. It isdesirable to incorporate sufficient amount of rapidly dispersingmicrogranules to coat extensively the esophageal mucosa. This creates acontent uniformity problem in these low-dose ODTs (for example, 300 mgODT containing 12 mg or less of a corticosteroid). Typically, thisproblem is overcome by granulation, which involves spraying a dilutesolution of the corticosteroid on to an excipient powder bed. The drugparticles are embedded in the granules and consequently may not becomeexposed to the inflamed mucosa, resulting in being poorly efficacious.It has been surprisingly observed possible not only to achieve desiredcontent uniformity but also enhance the probability of largely keepingthe corticosteroid drug particles exposed to the inflamed mucosa byadsorbing micronized topically acting corticosteroid drug particles ontothe pharmaceutically acceptable carrier (such as silicifiedmicrocrystalline cellulose) prior to blending with rapidly dispersingmicrogranules and other excipients and compressing into ODTs.

The dosage form as described herein may also include pharmaceuticallyacceptable excipients typically used in disintegrating tabletformulations such as fillers, diluents, glidants, disintegrants, bindersand lubricants.

Examples of suitable fillers, diluents and/or binders include lactose(e.g. spray-dried lactose, such as FAST-FLO®), microcrystallinecellulose (various grades of AVICEL®, CEOLUS®), hydroxypropylcellulose,L-hydroxypropylcellulose (low substituted), low molecular weighthydroxypropyl methylcellulose (HPMC) (e.g., METHOCEL™ E, F and K fromDow Chemical, MetholoseE SH from Shin-Etsu, Ltd), hydroxyethylcellulose,sodium carboxymethylcellulose, carboxymethylhydroxyethylcellulose andother cellulose derivatives, sucrose, agarose, sorbitol, mannitol,dextrins, maltodextrins, starches or modified starches (including potatostarch, maize starch and rice starch), calcium phosphate (e.g., basiccalcium phosphate, calcium hydrogen phosphate, dicalcium phosphatehydrate), calcium sulfate, calcium carbonate, sodium alginate andcollagen. The preferred filler for the composition of the invention ismannitol such as spray dried mannitol.

Examples of suitable disintegrants include crospovidone (cross-linkedPVP), sodium starch glycolate, cross-linked sodiumcarboxymethylcellulose, calcium silicate, and low substitutedhydroxypropyl cellulose. The preferred disintegrant for the compositionof the invention is cropovidone.

Specific examples of glidants and lubricants include stearic acid,magnesium stearate, calcium stearate or other metallic stearates, talc,glyceryl behenate, colloidal silica, corn starch, and optionallymagnesium stearate or sodium stearyl fumarate (lubricant intragranularlymixed or used externally to lubricate die and punch surfaces). Thepreferred glidant for the composition of the invention is colloidalsilica and preferred lubricant is sodium stearyl fumarate.

The solid pharmaceutical compositions of the present invention caninclude other dosage forms besides an ODT, a wafer, a film, or othersolid dosage form which disintegrates rapidly in the mouth to form asuspension or dispersion of a corticosteroid, which can readily beswallowed to coat the mucosal surface of eosinophilic esophagitis.

For example, wafers can include dried or lyophilized compositions suchas orally disintegrating or dissolving dosage forms prepared usingZYDIS® lyophilization technology (e.g., as described in U.S. Pat. No.6,316,027), containing a corticosteroid as the active pharmaceuticalingredient. Film dosage forms can include edible films such as thosedescribed in U.S. Pat. Nos. 6,596,298 or 6,740,332, containing acorticosteroid as the active pharmaceutical ingredient. In oneembodiment of the present invention the solid composition comprises alyophilized matrix, wherein the lyophilized matrix comprisescorticosteroid, the carrier and excipient. Suitable excipients includemannitol, xylitol, sorbitol, maltol, maltitol, lactose, sucrose,maltose, and combinations thereof.

Topical administration of a corticosteroid to the oral cavity ofindividuals has been associated with candidiasis infection. While theinvention is designed so as be less prone to promoting such aninfection, however in another embodiment of the invention, thepharmaceutical composition may include an antifungal agent. Suitableantifungal agents include, but are not limited to mitotic inhibitorantifungals, pyrimidine analog antifungals, polyene antifungals,benzimidazole antifungals, imidazole antifungals, polyene antifungals,triazole antifungals, thiazole antifungals, allylamine antifungals,echinocandin antifungals, and other “uncategorized” antifungalsrecognized in the art that do not fall within any of the abovecategories (e.g., tolnaflate and ciclopirox). For example, suitableantifungal agents which may be included in the solid pharmaceuticalcompositions of the present invention include abafungin, amorolfine,anidulafungin, bifonazole, butenafine, butoconazole, candicin,caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole,filipin, fluconazole, flucytosine, griseofulvin, isavuconizole,isoconazole, itraconazole, ketoconazole, micafungin, miconazole,miconazole nitrate, naftifine, natamycin, nystatin, oxiconazole,posaconazole, pramiconazole, ravuconazole, rimocidin, setaconizole,sulconazole, terbafine, terconazole, tioconazole, tolnaftate,undecylenic acid, and voriconazole.

In another embodiment, pharmaceutical compositions of the presentinvention include an antiviral agent. Antiviral agents which may beincluded in the solid pharmaceutical compositions of the presentinvention include interferons, nucleoside and nucleotide reversetranscriptase inhibitors, non-nucleoside reverse transcriptaseinhibitors, protease inhibitors, integrase inhibitors, fusioninhibitors, maturation inhibitors, guanosine analogs, puridine analogs,pyrimidine analogs, and other “uncategorized” antiviral drugs recognizedin the art which do not fall within any of the above classes (e.g.,foscarnet and miltefosine). For example, suitable antifungal agentswhich may be included in the solid pharmaceutical compositions of thepresent invention include abacavir, aciclovir (also known as acyclovir),adefovir, amantadine, amdoxovir, amprenavir, aplaviroc, apricitabine,arbidol, atazanavir, bevirimat, BMS-488043, boceprevir, brivudine,cidofovir, DCM205, docosanol, delavirdine, didanosine, durunavir,efavirenz, elvitegravir, elvucitabine, emtricitabine, enfuvirtide,epigallocatechin gallate, etravirine, famciclovir, fosamprenavir,ganciclocvir, globoidnan A, griffithsin, ibalizumab, idoxuridine,indinavir, lamivudine, lopinavir, loviride, maraviroc, nelfinavir,nevirapine, oseltamivir, pegylated interferon alpha-2a, pegylatedinterferon alpha-2b, penciclovir, peramivir, plerixafor, PRO 140,racivir, raltegrvir, ritonavir, ribavirin, rimantadine, rlipivirine,saquinavir, stampidine, stavudine, tenofovir, tipranavir, TNX-355,trifluridine, tromantadine, valaciclovir, valganciclovir, vicriviroc,vidarabione, viramidine, vivecon, zalcitabine, zanamivir, andzidovudine.

Tablet dosage forms, including ODT dosage forms, comprising the lowdosage strength of a topically acting corticosteroid and apharmaceutically acceptable carrier, wherein the drug is in amount lessthan about 5% (weight drug/weight of composition), have no significantsystemic glucocorticoid or mineralocorticoid activity after oraladministration in humans, disintegrate in less than about 30 sec (USPmethod), and have a low friability in order to have sufficientdurability to withstand handling, shipping, and/or packaging inpush-through blister packaging. Friability is less than about 1%, e.g.,less than about 0.9%, less than about 0.8%, less than about 0.7%, lessthan about 0.6%, less than about 0.5%, less than about 0.4%, less thanabout 0.3%, etc., inclusive of all ranges and sub-ranges there between).

Different preparation processes can be applied to prepare blends of acorticosteroid with suitable carrier having blend homogeneity, i.e.,acceptable blend uniformity and also content uniformity suitable fortableting. Blending the above ingredients can be achieved both by drymixing or by granulation.

The present invention further discloses the method of manufacturing oralcomposition, such as compression or compressible blend at a drug load offrom about 0.50 to about 3% by weight wherein it is challenging toachieve and maintain acceptable blend uniformity until the compressionor compressible blend is processed into final unit dosage forms (e.g.,orally disintegrating tablets) exhibiting acceptable content uniformity.The method comprises the following steps:

1) preparing the rapidly dispersing microgranules or granulate;

2) preparing the preblend 1 comprising charging a V-blender with onequarter of silicified microcrystalline cellulose (SMCC, apharmaceutically acceptable carrier), micronized corticosteorid,colloidal silicon dioxide (a glidant) and another quarter of SMCC andblending the contents for 10 minutes;

3) preparing the preblend 2 comprising charging a high shear granulatorwith a free flowing filler (such as spray dried mannitol), preblend 1,remaining half of SMCC, disintegrant (such as crospovidone), andsweetener (sucralose powder) and blending the contents for 10 minutes atan impeller speed of 300±50 rpm and a chopper speed of 1500±50 rpm;

4) preparing the final compressible blend comprising charging aV-blender with one half of the rapidly dispersing granules of step 1,lubricant (such as sodium stearyl fumarate), the pre-blend 2 of step 3,and remaining half of rapidly dispersing granules of step 1 and blendingfor 30 minutes, sampled and further blended for 10±1 minutes to achieveacceptable blend uniformity/homogeneity as per regulatory requirements;

5) preparing the orally disintegrating tablets comprising thecompressible blend of step 4, which exhibit acceptable contentuniformity as per regulatory requirements.

In one embodiment, the method of manufacturing orally disintegratingtablets is performed by repeated dry blending and milling. The methodcomprises the following steps:

1) preparing the rapidly dispersing microgranules or granulate with anaverage particle size of not more than about 400 μm by granulating oneor more sugar alcohols and/or saccharides, each having an averageparticle diameter of not more than about 30 μm, with a disintegrant(such as crospovidone) in presence of water or an alcohol-water mixtureand then drying the granulate (fluid-bed equipment or a conventionaloven);

2) preparing the milled preblend 1 by blending the pharmaceuticallyacceptable carrier (such as silicified microcrystalline cellulose),micronized corticosteroid and glidant (such as colloidal silicondioxide) in a V-blender for 10 minutes at 25±1 rpm and then millingthrough a comminuting mill equipped with a 024R screen (30 Mesh opening)at approximately 2400±100 rpm;

3) preparing the milled preblend 2 by blending half of free flowingmannitol, preblend 1 from step 2, disintegrant (crospovidone), andsweetener (sucralose powder) in a V-blender for 10 minutes at 25±1 rpmand then milling through a comminuting mill equipped with a 024R screenat a speed of 2400±100 rpm, and rinsing the mill with remaining half offree flowing mannitol;

4) preparing the compressible blend by blending the rapidly dispersinggranules of step 1, lubricant (such as sodium stearyl fumarate), themilled preblend 2 of step 3, rinsed free flowing mannitol) for totaltime of 40 minutes;

5) preparing the tablets by compressing the compressible blend of step4.

The repeated dry blending and milling process is the preferred processfor the preparation of the compositions of the invention.

In the process of the invention the different steps and the order ofaddition of individual components is important to achieve as acceptableblend uniformity/homogeneity in the compressible blend, as well asacceptable content uniformity of the finished dosage units as perregulatory requirements. The tablets obtained with the above processhave the appearance, disintegration time, hardness and friabilityappropriate and suitable for ODTs to withstand attrition duringtransport in bulk containers, commercial packaging in blisters orbottles, and transport of primary/secondary packaged products forcommercial distribution and end use and the purpose of the invention.Moreover, the tablets manufactured and then packaged in blisters arehighly stable at accelerated and long-term ICH stability conditions.

The solid pharmaceutical compositions of the present invention aresuitable for oral administration of a topically acting corticosteroid totreat inflamed tissues of the upper gastrointestinal tract, for examplethe esophagus. The use of a topically acting corticosteroid for treatingconditions associated with inflammation of the gastrointestinal tract isdesirable because it results in fewer side-effects than a highlysystemically acting corticosteroid.

Inflammatory conditions of the gastrointestinal tract which may betreated according to the present invention include inflammation of theesophagus, inflammation of the glottis, inflammation of the epiglottis,inflammation of the tonsils, inflammation of the oropharynx,eosinophilic esophagitis, gastroesophageal reflux disease (GERD),non-erosive reflux disease (NERD), erosive esophagitis, Barrett'sesophagus, eosinophilic gastroenteritis, hypereosinophilic syndrome,corrosive (caustic) chemical esophagitis, radiation-induced esophagitis,chemotherapy-induced esophagitis, transient drug-induced esophagitis(also known as medication esophagitis), persistent drug inducedesophagitis, Crohn's disease of the esophagus, and pseudomembranousesophagitis.

In one specific embodiment, the pharmaceutical compositions of thepresent invention are suitable for treating inflammatory conditions ofthe upper gastrointestinal tract, particularly eosinophilic esophagitis.

Thus, the present invention includes pharmaceutical composition for useas medicaments in the treatment of inflammatory conditions of thegastrointestinal tract.

The invention also includes the method of administering to a patient inneed thereof a solid pharmaceutical composition of the presentinvention. In one embodiment, the present invention includes a methodfor treating eosinophilic esophagitis comprising administering to apatient in need thereof a pharmaceutical composition of the presentinvention. Upon administration of a solid pharmaceutical composition ofthe present invention to an individual, the composition disintegrates inthe patient's oral cavity. In another embodiment, the present inventionincludes a method for treating gastroesophageal reflux disease (GERD),nonerosive reflux disease (NERD) or erosive esophagitis comprisingadministering to an individual in need thereof a pharmaceuticalcomposition of the present invention. In another embodiment, the presentinvention includes a method for treating a food allergy with anidentified allergen, e.g., “atopic IBS”, and “atopic bowel”.

From the foregoing description and the experimental part, it can be seenthat the present invention provides several important advantages. Thedescribed invention provides low dose oral compositions comprising acorticosteroid and a pharmaceutical carrier characterized by highcontent uniformity and stability, the composition and dosage formswherein the corticosteroid microparticles are present largely at or nearthe surface of the carrier and are therefore likely to be suitablypositioned for the topical treatment of inflammation of gastroenterictract, particularly EoE, upon disintegration of the corticosteroid ODTin the oral cavity of a patient and swallowing of the resultant viscoussuspension.

Experiments Methods

Bulk/tapped density is measured according to USP <616> method 1.

Particle size distribution (PSD) is measured on samples of 5-10 mg withATM sonic sifter.

Flowability is tested using Sotax flow tester on about 110 g ofmaterials employing standard six pre-vibration/vibration mode; the flowproperty is expressed as a flow index (α′/α_(ref)) and as Carr's index.

Water content is determined using Karl Fisher titration or LOD ismeasured according to USP<921>1a method.

Blend Uniformity Testing: Blend uniformity testing is carried out bywithdrawing 6 random samples using a sampling thief from differentlocations of the final direct compression blend contained in the V- ortwin shell blender as shown in FIG. 1. Samples collected are tested fortheir drug contents using an HPLC stability-indicating method.

Content Uniformity of ODTs: Orally disintegrating tablets are randomlysampled at the beginning, middle and end of each compression run, 10tablets are tested for their content uniformity using the HPLCstability-indicating method.

Disintegration is performed according to USP<701> method. Friability ismeasured according to USP<1216> method.

EXAMPLES Example 1: Rapidiy Dispersing Microgranules

Rapidly dispersing microgranules are prepared following the proceduredisclosed in US Patent Application Publication No. U.S. 2003/0215500published Nov. 20, 2003, the contents of which are hereby incorporatedby reference in its entirety for all purposes. Specifically, D-mannitol(152 kg) with an average particle size of approximately 20 μm or less(PEARLITOL® 25 from Roquette, France) is blended with 8 kg ofcross-linked povidone (CROSPOVIDONE® XL-10 from ISP) in a high sheargranulator (GMX 600 from Vector), granulated with purified water(approximately 32 kg), wet-milled using a Comil from Quadro, and finallytray-dried to provide microgranules having an LOD (loss on drying) ofless than about 1.0%. Alternatively, the wet milled granules are driedin a fluid-bed dryer to provide microgranules having an LOD of less than1.0% by weight. The dried granules are sieved and oversize material isagain milled to produce rapidly dispersing microgranules with an averageparticle size in the range of approximately 175-300 microns.

D-mannitol with a median particle size of <20 μm (93 parts) andCrospovidone (5 parts) are granulated by spraying the starch solution (2parts of STARCH 1500® from Colorcon) in a top spray fluid-bed granulatorand dried for a loss on drying of <1.0%. The dried granules are sievedthrough a 20 mesh sieve, and oversized granules are milled and sieved,if needed to produce alternate rapidly dispersing granules.

Example 2: Blend Preparation by High Shear Process for 1.5 mgFluticasone ODT; Batch 1

A preblend 1 is first prepared by blending one quarter of silicifiedmicrocrystalline cellulose (SMCC commercially available as PROSOLV®HD90), micronized fluticasone propionate, colloidal silicon dioxide, andanother quarter of SMCC in a 1 quart V-blender for 10±1 minutes (seeTable 1 for weights of individual components of compressible blends ofODTs, 1.5 and 3 mg). A second preblend (preblend 2) is prepared: 10 Lgranulation bowl of a high shear granulator, PMA 1 is charged withspray-dried mannitol (PARTECK® M200), preblend 1, remaining half ofSMCC, crospovidone and sucralose powder. Blending is performed for 10±1minutes at an impeller speed of 300±50 rpm and a chopper speed of1500±50 rpm to produce preblend 2. One half of rapidly dispersingmicrogranules, sodium stearyl fumarate, preblend 2 and the remaininghalf of rapidly dispersing microgranules are blended in a 8 qt V shellblender and sampled for blend uniformity at 30 and 40 minutes. The finalblend is sampled for bulk/tapped density, particle size distribution(PSD), flowability and moisture testing.

TABLE 1 Compositions of compressible blends of Fluticasone ODT's, 1.5and 3 mg Fluticasone ODTs ODT Batch # 1.5 mg 1.5 mg 1.5 mg 1.5 mg 3 mg 3mg batch 1 batch 2 batch 3 batch 4 batch 5 batch 6 (%/ (mg/ (mg/ (mg/(mg/ (%/ (mg/ (mg/ Ingredients (mg) tablet) tablet) tablet) tablet)tablet) tablet) tablet) tablet) Micronized Fluticasone 0.50 1.50 1.501.50 1.50 1.0 3.00 3.00 Propionate USP Colloidal Silicon Dioxide NF 0.300.90 0.90 0.90 0.90 0.30 0.90 0.90 Colloidal Microcrystalline 10.0030.00 30.00 30.00 30.00 10.00 30.00 30.00 Cellulose NF Crospovidone NF7.50 22.50 22.50 22.50 22.50 7.50 22.50 22.50 Sucralose NF 0.40 1.201.20 1.20 1.20 0.40 1.20 1.20 Spray-dried Mannitol USP 30.30 90.90 90.9090.90 89.40 29.80 89.40 87.90 Rapidly Dispersing Granules 50.00 150.00150.0 150.0 150.0 50.00 150.0 150.0 Sodium Stearyl Fumarate NF 1.00 3.003.00 3.00 4.50 1.00 3.00 4.50 Total 100.00 300.0 300.0 300.0 300.0 100.0300.0 300.0

Example 3: Blends Preparation by Repeated Blending and Milling for 1.5and 3 mg Fluticasone ODT; Batch 2, 3 5

A preblend 1 (see Table 1 for weights of individual components ofcompressible blends of ODTs, 1.5 and 3 mg) is prepared by charging a 2quart V-blender sequentially with half of SMCC, micronized fluticasonepropionate, colloidal silicon dioxide and the remaining half of SMCC andblending for 10±1 minutes. The preblend 1 is passed through a QUADROComil fitted with a 024R screen (30 mesh opening) at approximately2400±100 rpm. Preblend 2 is prepared: half of spray-dried mannitol,milled preblend 1, crospovidone, and sucralose powder are blended in a 4quart V-blender for 10±1 minutes and milled through the 024R screen. TheComil is rinsed by passing the remaining half of spray-dried mannitolthrough a 024R screen. Half of rapidly dispersing microgranules, sodiumstearyl fumarate, milled preblend 1, rinsed mannitol and the remaininghalf of rapidly dispersing granules arc blended and sampled for blenduniformity at 30 and 40 minutes. The final blends are sampled fortesting of bulk/tapped density, particle size distribution (PSD),flowability, and moisture content.

Example 4: Blend Uniformity Results of Blends of Examples 2 and 3

Test results for the compressible blends of Examples 2 and 3 arepresented in Table 2. The compression blends, ODT 1.5 mg (batch 1) andODT 1.5 mg (batch 2), which have been processed using two differentcombinations of equipment—V-blender-high shear granulator andV-blender-comminuting mill—show similar blend physical (powder)properties such as bulk and tapped densities, particle sizedistributions, flow properties, and blend uniformity values, exceptingthat the 30-minute blended batch shows a slightly higher % RSD.

TABLE 2 Physical/Blend uniformity test results for Fluticasone ODT, 1.5and 3 mg Compressible Blends Blend Batch# 1.5 mg 1.5 mg 1.5 mg 3 mg 1.5mg 3 mg Test Parameters batch 1 batch 2 batch 3 batch 5 batch 4 batch 6Bulk/Tap Bulk Density 0.57 0.57 0.57 0.57 0.57 0.58 Density TappedDensity 0.71 0.71 0.72 0.70 0.78 0.77 USP <616> Method I Particle % % %% % % Sieve # Size (μm) Retained Retained Retained Retained RetainedRetained Particle Size  20 840 0.62 0.39 0.36 0.61 0.6 0.4 Analysis  40425 16.08 14.05 17.32 18.08 18.9 20.2  60 250 13.37 12.00 14.57 14.6213.8 14.8  80 180 9.70 10.33 10.07 10.21 10.7 12.0 100 150 6.60 5.847.90 8.37 6.2 5.5 200  75 22.61 24.62 19.83 21.24 20.0 20.0 Pan  2031.01 32.77 29.95 26.86 29.8 27.1 LOD USP <921> 1a 1.0 1.0 1.0 0.9 1.01.1 Parameters Flow Results Flow Angle 67.9 69 55.7 55.9 68.5 67.3 FlowIndex 0.83 0.84 0.68 0.68 0.84 0.82 Flow Quality Good Good Medium MediumGood Good Bend Uniformity Blending 30 40 30 40 30 40 40 40 time min minmin min min min min min Minimum, %  94.8  94.5 93.2 93.4  95.8 101.094.7 97.3 Maximum, % 105.1 100.4 98.6 99.9 102.8 104.8 99.4 101.1 Mean,%  99.3  97.2 95.7 97.0  98.9 102.0 97.4 99.5 % RSD  3.6  2.2  2.0  2.9 2.7  1.4 1.0 1.5 Content Mean 101.5 101.1 100.6 100.7 Uniformity ±SD3.7 1.5 2.0 1.0 AV 8.8 3.7 4.7 2.4

TABLE 3 Stratified Blend uniformity results for Fluticasone ODTCompression Blends Label Claim (%) 1.5 mg 1.5 mg 1.5 mg 3 mg 3 mgSampling 101 201 301 101 201 Location 30 min 40 min 30 min 40 min 40 min30 min 40 min 40 min Top Left 98.9 96.0 95.9 99.9 94.7 100.6 101.5 98.0Middle Left 105.1 94.5 93.2 93.4 98.2 100.0 101.6 99.9 Bottom Left 101.297.8 95.5 99.0 95.5 102.8 104.8 97.3 Top Right 94.8 95.9 94.1 93.6 98.596.4 101.7 101.1 Middle Right 98.3 100.4 98.6 98.2 99.4 95.8 101.0 99.5Bottom Right 97.4 98.7 96.8 97.6 97.8 98.0 101.6 100.9 Maximum 105.1100.4 98.6 99.9 99.4 102.8 104.8 101.1 Minimum 94.8 94.5 93.2 93.4 94.795.8 101.0 97.3 Mean 99.3 97.2 95.7 97.0 97.4 98.9 102.0 99.5 RSD 3.6%2.2% 2.0% 2.9% 1.9% 2.7% 1.4% 1.5%

Example 5: Compression of ODTs of Examples 2 and 3

The compression blends of Examples 2 and 3 are compressed using a rotarytablet press, Manesty Beta Press equipped with 8 punch die sets of 9.5mm round, plain, flat-faced radius edge tooling. The average tabletweight is about 300 mg. The main compression force used is maintained at5-6 KN, with a pre-compression force set at 2±0.2 kN for compressionruns (except where noted). During the compression, the tablet pressinstrumentation by SMI is used to measure press speed and compressionforce. During tableting, tablets are periodically sampled for visualinspection of ‘appearance’, in-process measurements of weight,thickness, hardness and friability. Additional tablets are also samplesas ‘composite samples’ for analytical testing. Details of compressionparameters and tablet properties are shown in Table 4. Tablets appearsas round tablets they are also tested for assay, potency, contentuniformity, dissolution (greater than 90% release after 45 minutes forall batches); they have friability not more than 0.4%, hardness of about4 kP, disintegration time less than 30 sec.

Example 6: Confirmatory Compression Blend and ODT Batches (ODT 1.5 mg:Batch 3, 3 mg: Batch 5)

Blend batches preparation by a twice repeated blending and millingprocess (repeated process of blending in the V-shell blender inconjunction with the milling using the Comil) for 1.5 and 3.0 mgfluticasone ODTs compression blends (see Table 1 for compositions, andTables 2 and 3 for Physical/Blend uniformity test results and StratifiedBlend uniformity results, respectively). Although bulk and tappeddensity values, particle size distributions blend uniformity values forthe confirmatory compression blends are similar to those of thecorresponding attributes of the ODT compression blend batch, ODT 1.5 mg(batch 2), the estimated flow properties of both ODT 1.5 mg (batch 3)and ODT 3 mg (batch 5) are not very good. Both compression blend batchesare compressed using the same Beta Press equipped with the same set oftooling, and under comparable compression parameters. During compressionof both compression blends, some picking and/or sticking to the punchesis observed. Details of compression parameters and tablet properties areshown in Table 4.

Example 7: Blends Preparation by Repeated Blending and Milling for 1.5and 3 mg Fluticasone ODT, Lubricant at 1.5% by Weight, Batches 4 and 6

Fluticasone compression blend batches are prepared by first preparingpreblend 1 and preblend 2 as disclosed in Example 3, then blending thecomponents of the final blend without incorporating the lubricant for 35minutes and further blending for 5 minutes following the addition of thelubricant (sodium stearyl fumarate at 1.5% by weight). The final blendsare sampled for testing of bulk and tapped density, particle sizedistribution (PSD), flowability, moisture content, blend uniformity, andstratified blend uniformity of both batches. Results are reported inTables 2 and 3.

Example 8: Compression of ODTs of Example 7

Both batches are compressed using the same rotary tablet press, same setof tooling and under similar compression conditions as disclosed above.

TABLE 4 Compaction process conditions chemical/physical test results forFluticasone ODTs 1.5 mg tablet 3 mg tablet Compression 1.5 mg 1.5 mg 1.5mg 1.5 mg 3 mg 3 mg parameters batch 1 batch 2 batch 3 batch 4 batch 5batch 6 Compression force (kN) 5.1-5.5 5.1-6.0 5.3-5.8 5.5-6.0   5.14.7-6.0 Precompression force 2.1-2.2   2.2 2.0-2.2  0   2.0  0 (kN)Results Average weight (mg) 304.3 ± 3.2  305.4 ± 3.4  303.8 ± 0.7  304.7± 3.3   307 ± 2.1  301.8 ± 2.1  Hardness min-max (kp) 3.23-4.01 3.0-3.92.67-4.12 3.8-3.6 3.00-3.85 3.0-4.2 Thickness min-max (mm) 4.059-4.1494.02-4.23 4.09-4.21 4.13-4.19 4.28-4.33 3.99-4.15 Friability (%)    0.29   0.24    0.63    0.64    0.52    0.27 Disintegration - Start (sec) 1213 12 12 10 14 Disintegration - End (sec) 14 14 12 24 16 15 Assay %label claim n.p.  100.0 n.p.   99.2  103.8  101.6 Related Substances (%)n.p. n.p. n.p. n.p. n.p. n.p. Unknown n.p. n.p. n.p.   <0.10   <0.10  <0.10 Unknown n.p.    0.11 n.p. n.p. n.p. n.p. Total n.p.    0.11 n.p.  <0.10   <0.10   <0.10 Dissolution (% at x minutes) 10 63 52 69 67 5454 20 79 81 86 83 73 73 30 87 91 93 89 84 82 45 92 95 96 93 91 88 60 9596 98 94 94 90 N.P. ---> not performed

Example 9: Stability Testing

Fluticasone ODT batches 2 (1.5 mg) and 5 (3 mg) are packaged in 30 cc(30 tablets per bottle) HDPE bottles, with rayon coil and 0.5 g pouchdessicant (Sorb-it ½ g packet) included. All ODTs are stable ataccelerated conditions (40° C./75%·RH) for a period of 6 months, as wellas at long-term stability conditions (25° C./60% RH) for a period of 9months as shown in Tables 5 and 6. The physical properties, such asappearance, hardeness, friability, and disintegration time at allstability conditions are also comparable to the initial values ofFluticasone ODTs, 1.5 and 3 mg.

TABLE 5 Stability data for Fluticasone ODT batch 2 (1.5 mg) Batch 2, 1.5mg Test/ Time = 6 months Time = 9 months Method Time = Initial 40°C./75% RH 25° C./60% RH Physical White round tablets White round tabletsWhite round tablets Appear- ance/ Visual Moisture 1.0% 1.9% 1.8% Disin-16 sec 25 sec 18 sec tegration Friability 0.3% 0.6% 0.1% Hardness Min:2.2 Min: 1.4 Min: 2.7 (kP) Max: 3.6 Max: 3.3 Max: 4.3 Mean: 3.0 Mean:2.5 Mean: 3.4 Potency 1: 100.0 1: 100.0 1: 99.5 (%) 2: 100.0 2: 100.2 2:98.3 Mean: 100.0 Mean: 100.1 Mean: 98.9 Related RRT % RS RRT % RS RRT %RS Sub- stances, Unknown — — 0.89 0.14 1.66 0.10 Unknown 0.75 0.11 0.900.13 — — Total (%) 0.11 0.27 0.10 Disso- lution Minutes 10 20 30 45 6010 20 30 45 60 10   20   30   45   60   Minimum 61 82 90 93 95 66 84 9296 97 66   83   90   93   94   (%) Maximum 67 86 94 97 99 68 86 93 97 9969   85   91   95   96   (%) Mean (%) 64 85 92 95 97 67 85 92 96 98 67  84   91   94   95   % RSD   3.3   2.1   1.7   1.7   1.7   1.0   0.7  0.7   0.8   0.8  1.8  0.9  0.8  0.8  0.8

TABLE 6 Stability data for Fluticasone ODT batch 5 (3 mg) Batch 5, 3 mgTest/ Time = 6 months Time = 9 months Method Time = Initial 40° C./75%RH 25° C./60% RH Physical White round tablets White round tablets Whiteround tablets Appear- ance/ Visual Moisture 0.9% 1.3% 1.8% ContentDisin- 17 sec 17 sec 15 sec tegration Time Friability 1.2% 1.6% 1.1%Hardness Min: 1.9 Min: 1.3 Min: 1.7 (kP) Max: 3.5 Max: 3.7 Max: 3.0Mean: 2.6 Mean: 2.5 Mean: 2.4 Potency 1: 103.6 1: 99.8 1: 100.7 (%) 2:103.9 2: 97.4 2: 100.1 Mean: 103.8 Mean: 98.6 Mean: 100.4 Related RRT %RS RRT % RS RRT % RS Sub- stances, Unknown 0.89 <0.1 0.89 0.14 1.66 0.13Unknown — — 0.90 0.13 — — Total (%) <0.1 0.27 0.10 Disso- lution Minutes10 20 30 45 60 10 20 30 45 60 10   20   30   45   60   Minimum 57 78 8792 94 47 64 72 78 80 56   76   85   91   93   (%) Maximum 61 81 90 95 9756 76 89 97 101 59   78   89   96   99   (%) Mean (%) 59 79 88 94 96 5373 84 91 94 58   77   86   93   95   % RSD   3.1   1.7   1.4   1.4   1.3  6.1   6.4   7.0   7.4   7.6  1.5  1.2  1.7  2.0  2.2

Example 10: Preparation of Clinical Trial Materials, Batches C1, C2

Clinical trial batches (Fluticasone propionate ODTs, 1.5 and 3 mg with1.5% by weight of sodium stearyl fumarate) are prepared by a repeatedblending-milling-blending process followed by compression as disclosedin Examples 7 and 8. The in-process testing results and the analyticalresults of the clinical batches are presented in Table 7 and Table 8,respectively. The compression blend batches show physical (powder)properties similar to that of the feasibility batches, except that theclinical batches have more finer particles passing through 100 meshsieve (67-76% particles are <150 μm in size) as compared to 47-57%)finer particles in the feasibility batches. However, this has notaffected the tableting properties of the clinical batches significantly;in batch C-2 (3 mg) a slightly higher % RSD In content uniformity andexcellent blend uniformity results are observed.

TABLE 7 Physical/Blend uniformity test results for Clinical TrialBatches 1.5 and 3 mg Test/ 1.5 mg Blend 3 mg Blend Method Test Parameter1.5001 1.5002 3.0001 3.0002 Bulk/Tap Bulk Density (g/cc) 0.56 0.56 0.560.56 Density Tapped Density 0.75 0.75 0.75 0.74 USP <616> (g/cc) Method1 Hausner Ratio 1.34 1.34 1.34 1.32 Carr's Index 25.14 25.41 25.56 24.44Particle Size % % % % Size/ (μm) Retained Retained Retained RetainedParticle Size  20 840 0.50 0.80 0.20 0.70 Analysis  40 425 2.90 3.307.30 3.40  60 250 6.00 10.60 5.10 9.90  80 180 8.90 11.40 9.30 10.80 100150 5.50 6.00 6.10 5.70 200  75 23.20 23.40 24.40 21.40 Pan <75 53.0044.50 52.60 48.10 LOD (USP <921>1a 1.3 1.2 1.6 1.2 Blend Minimum (%)97.4 94.0 96.4 94.1 Uniformity Maximum (%) 98.1 97.0 99.1 96.2 Mean (%)97.9 96.1 98.1 95.8 % RSD 0.3 1.2 0.9 0.9

TABLE 8 Physical/Blend uniformity test results for Clinical TrialBatches of Fluticasone ODTs, 1.5 and 3 mg Parameter ODT 1.5 mg C1 ODT1.5 mg C2 ODT 3 mg C1 ODT 3 mg C2 Physical Appearance/ White round Whiteround White round White round Visual tablets tablets tablets tabletsMoisture Content 1.9% 1.2% 1.8% 1.3% Disintegration Time 15 sec 18 sec16 sec 19 sec Friability 0.1% 0.0% 0.4% 0.3% Hardness, kP Min: 3.1Minimum: 3 9 Minimum: 2 8 Minimum: 3 5 Max: 5.1 Maximum: 5.4 Maximum:4.3 Maximum: 4.9 Mean: 3.9 Mean: 4.6 Mean: 3.4 Mean: 4.3 Potency (%) 1:98.3 1: 95.4 1: 98.3 1: 98.1 2: 99.2 2: 96.1 2: 99.6 2: 97.9 Mean: 98.8Mean: 95.8 Mean: 99.0 Mean: 98.0 Related Substance (%) % RS at RRT % RSat RRT % RS at RRT % RS at RRT Individual Impurity <0.1% at 0.89 <0.10<0.10 <0.10 Total (NMT 1.5%) <0.1% at 0.90 <0.10 <0.10 <0.10 ContentUniformity of 97.0 93.2 98.3 96.1 Dosage units - Minimum (%) — Maximum99.3 97.9 100.4 98.5 — Mean 98.1 96.3 99.2 97.5 — % RSD  2.3  6.1  1.7 3.7 % Mean Dissolved/60 96% 95% 94% 93% min

Example 11: Stability Data for Clinical Trial Batches, Fluticasone ODTs,1.5 and 3 mg

Fluticasone ODT batches, 1.5 mg and 3 mg are packaged in 30 c′t (30tablets per bottle) HDPE bottles, with rayon coil and 0.5 g pouchdessicant (Sorb-it ½ g packet) included. All ODTs are stable ataccelerated conditions (40° C./75% RH) for a period of 9 months, as wellas at long-term stability conditions (25° C./60% RH) for a period of 24months as shown in Table 9. The physical properties, such as appearance,hardness, friability, and disintegration time at all stabilityconditions are also comparable to the initial values of FluticasoneODTs, 1.5 and 3 mg.

TABLE 9 Stability data for Clinical Trial Batches Fluticasone ODTs, 1.5and 3 mg ODTs 1.5 mg ODTs, 3 mg ODT Batch # Time: 24 months Time: 24months Parameter Time: Initial at 25° C./60% RH Time: Initial at 25°C./60% RH Physical Appearance/ White round White round White round Whiteround Visual tablets tablets tablets tablets Moisture Content 2.2% 2.1%2.4% 2.0% Disintegration Time 0-5 sec 0-5 sec 0-5 sec 0-5 sec Friability0.03% 0.12% 0.02% 0.50% Hardness, kP Min: 3.6 Min: 3.8 Min: 4.0 Min: 3.3Max: 6.1 Max: 5.9 Max: 5.9 Max: 6.2 Mean: 4.8 Mean: 5.0 Mean: 4.7 Mean:4.8 Potency (%) 1: 100.8 1: 99.7 1: 100.3 1: 100.0 2: 100.3 2: 99.8 2:101.3 2: 100.0 Mean: 100.6 Mean: 99.7 Mean: 100.8 Mean: 100.0 RelatedSubstances % RS at RRT % RS at RRT % RS at RRT % RS at RRT Unknown <0.1%at 0.89 — <0.1% at 0.89 — Unknown <0.1% at 0.90 — <0.1% at 0.90 — Total<0.1 <QL <0.1 <QL % Mean Dissolved/ 96% 95% 94% 93% 60 min

Example 12: Clinical Tests

A proof of concept study is conducted for clinical batches ODT-FT 1.5 mgand 3 mg dose strengths in patients with a diagnosis of EoE aged 12years to 55 years.

The doses utilized are 1.5 mg administered twice daily and 3.0 mgadministered once daily. The study also included a placebo arm. Each armenrolls 8 subjects. Findings of efficacy analyses demonstrate a positivesignal for efficacy with the greatest response seen histologically inthe decrease of peak eosinophil count per high power field (a hallmarkof the disease and indicator of treatment response). Both 1.5 mg and 3mg treatment groups are clearly more efficacious than placebohistologically. The percent of subjects with at least 30% decrease inthe overall EoE symptom severity, as measured by patient questionnaire,also shows numerical superiority of the two FT-ODTs over placebo.Endoscopic improvements are also seen with changes in furrowing andvascularity showing the greatest differentiation of FT-ODTs fromplacebo, indicating a positive anti-inflammatory effect of theformulations.

Overall, the FT-ODTs of the invention demonstrate improvements inhistology, overall symptoms and overall endoscopic activity.

Example 13: Preparation of Blends for 0.75, 4.5 and 6 mg FluticasoneODTs—Batches 7 to 9

Fluticasone compression blend batches at a drug load of 0.25% by weightare prepared by first preparing preblend 1 and pre blend 2 as disclosedin Example 3. A preblend 1 (see Table 10 for weights of individualcomponents of compression blends of ODTs, 0.75 mg, 4.5 mg and 6 mg) isprepared by charging a 2 quart V-blender sequentially with half of SMCC,micronized fluticasone propionate, colloidal silicon dioxide and theremaining half of SMCC and blending at 25 rpm for 10±1 minutes. Thepreblend 1 is passed through a QUADRO Comil fitted with a 024R screen(30 mesh opening) at approximately 2400±100 rpm. Preblend 2 is prepared:half of spray-dried mannitol, milled preblend 1, crospovidone, andsucralose powder are blended in a 32 quart V-blender at 25 rpm for 10±1minutes and milled through the 024R screen. The Comil is rinsed bypassing the remaining half of spray dried mannitol through a 024Rscreen. Half of rapidly dispersing microgranules, milled preblend 1,rinsed mannitol and the remaining half of rapidly dispersing granulesare blended in a 32 quarts V-blender at 25 rpm, without incorporatingthe lubricant, for 35 minutes and further blended for 5 minutesfollowing the addition of the lubricant (sodium stearyl fumarate at 1.5%by weight).

Example 14: Preparation of Blends for 1.5 mg Fluticasone ODTs at BatchSize: 30 Kgs; Batch 10

The manufacturing process for the fluticasone compression blend batch ata lower drug load of 0.5% by weight is scaled up to a semi-industrialscale of 30 kgs. The process essentially consists of first preparingpreblend 1 and preblend 2 as disclosed in Example 3. A preblend 1 (seeTable 10 for weights of individual components of compressible blends ofODTs, 1.5 mg) is prepared by charging a 32 quart V-blender sequentiallywith half of SMCC, micronized fluticasone propionate, colloidal silicondioxide and the remaining half of SMCC and blending at 25 rpm for 10±1minutes. The preblend 1 is passed through a QUADRO Comil fitted with a024R screen (30 mesh opening) at approximately 2400±100 rpm. Preblend 2is prepared: half of spray-dried mannitol, milled preblend 1,crospovidone, and sucralose powder are blended in a Galley blender with113 L tote at 12 rpm for 20±1 minutes and milled through the 024Rscreen. The Comil is rinsed by passing the remaining half of spray-driedmannitol through a 024R screen. Half of rapidly dispersingmicrogranules, milled preblend 1, rinsed mannitol and the remaining halfof rapidly dispersing granules are blended at 12 rpm for up to 40minutes.

The final blends in Example 13 and 14 are sampled and subjected toin-process testing as per United States Pharmacopeia requirements andanalytical testing of bulk and tapped density, particle sizedistribution (PSD), flowability, blend uniformity and moisture content.This is the first time, a direct compression ODT blend batch at a drugload of 0.25% by weight is manufactured using the procedure establishedfor the blend at a drug load of 0.5% by weight. No technical issues havebeen encountered during the manufacture. The results reported in Table11 show acceptable physical characteristics. Although the blenduniformity data indicate a uniform distribution of the active, a lowpotency is evident in Batch 7 with the lowest drug load, probably due toa loss of the active during blending/milling. During the semi-industrialscale compression blending process prior to incorporating the lubricant,the blends sampled at 20, 30 and 40 minutes show acceptable blenduniformity values as shown below.

Blend Sampling Time 20 min 30 min 40 min Uniformity (% Mean (%) 101.499.1 98.3 Label Claim) Minimum (%) 99.3 97.2 95.9 Maximum (%) 104.3100.6 100.1 RSD (%) 1.4 1.4 1.3

Example 15: Compression of ODTs of Example 13 and 14

Batches of ODTs, 0.75 mg, 4.5 mg and 6 mg are compressed using the samerotary tablet press (Beta Press) equipped with the same force feeder andsame set of tooling (B-size tooling, 9.5 mm round flat faced radiusedge) and under similar compression conditions as disclosed previouslyfor ODTs, 1.5 mg or 3 mg. The compressed tablets of 0.75 mg, 4.5 mg and6 mg meet the specifications for tablet weight, disintegration time,friability, hardness and thickness. The physical properties of thetablets are similar and comparable to the other dose strengths. Thepotency and content uniformity results for the 0.75 mg ODTs indicate alow potency confirming the low blend uniformity results reported above.

ODTs, 1.5 mg are compressed using the industrial tablet press, Korsch XL400 equipped with D tooling, 9.5 mm round, flat faced radius edge,operated at 1015 tablets per minutes. The compressed tablets areobserved to meet all specifications for tablet weight, disintegrationtime, friability, hardness and tablet thickness. The physical propertiesof the tablets are similar and comparable to the same dose strength orother dose strengths produced at small scale. The potency and contentuniformity results confirm the blend uniformity results, resulting ODTsmeeting all product specifications. The results of the scale up batchhave shown that the current small-scale process at a drug load of 0.5%by weight or higher, is scalable. The comparable/similar resultsobtained between dose strengths and consistency in results between batchsizes at least at a drug load of 0.5% by weight or higher, indicate arobust, suitable direct compression manufacturing process for ODT dosestrengths ranging from 1.5 mg to 6 mg or at a drug load of from 0.5%, to2% by weight. This low-end drug load has been possible in the past onlyby spray granulation, by spraying the drug solution while granulatingtablet components excepting the lubricant.

TABLE 10 Compositions of compression blends of Fluticasone ODTs, 0.75 mg(Batch 7), 4.5 mg (Batch 8), 6 mg (Batch 9) and 1.5 mg (Batch 10)Fluticasone ODTs Ingredients 0.75 mg 4.5 mg 6.0 mg 1.5 mg (mg) batch 7batch 8 batch 9 batch 10 ODT (%/ (mg/t (mg/ (mg/ (mg/ Batch # tablet)ablet) tablet) tablet) tablet) Micronized 0.25 0.75 4.50 6.00 1.50Fluticasone Propionate USP Colloidal 0.30 0.90 0.90 0.90 0.90 SiliconDioxide NF Silicified 10.00 30.0 30.00 30.00 30.00 MicrocrystallineCellulose NF Crospovidone NF 7.50 22.50 22.50 22.50 22.50 Sucralose NF0.40 1.20 1.20 1.20 1.20 Spray-dried 30.05 90.15 86.40 84.90 89.40Mannitol USP Rapidly 50.00 150.00 150.00 150.0 150.0 Dispersing GranulesSodium Stearyl 1.50 4.50 4.50 4.50 4.50 Fumarate NF Total 100.00 300.00300.00 300.00 300.00

TABLE 11 Physical/Blend uniformity test results for Fluticasone ODT,0.75 mg, 4.5 mg and 6 mg Compression Blends Blend Batch # 0.75 mg 4.5 mg6.0 mg Test Parameters batch 7 batch 8 batch 9 Bulk/Tap Density BulkDensity 0.56 0.55 0.55 USP <616> Tapped Density 0.75 0.73 0.75 Method IHausner Ratio 1.33 1.33 1.33 Particle Size % % % Sieve # (μm) RetainedRetained Retained Particle Size 20 840 0.6 0.6 0.6 Analysis 40 425 10.09.8 7.6 60 250 16.9 16.7 15.1 80 180 20.2 19.2 18.5 100 150 9.3 9.3 9.4200 75 25.2 26.9 28.4 Pan 20 17.8 17.5 20.5 LOD USP<921>(KF) 1.4 1.8 1.5Flow Results Flow Angle 82.6 83.9 83.2 Flow Index 1.01 1.02 1.01 FlowQuality Very Good Very Good Medium Blend Uniformity Blending Time Blend(40 min) After Lubrication Mean, % 91.3 97.1 98.7 Minimum, % 88.5 94.794.7 Maximum, % 94.1 98.7 100.4 % RSD 2.2 1.3 2.1

TABLE 12 Compaction process conditions and chemical/physical testresults for Fluticasone ODTs ODTs 0.75 mg 4.5 mg 6.0 mg 1.5 mgCompression parameters batch 7 batch 8 batch 9 batch 10 Compressionforce (kN) 5.3-5.6 5.0-5.2 5.2-5.3 4.8-5.1 Precompression force (kN) 2.01.5-1.7 1.5 1.3-1.4 Average weight, mg (% RSD)* 302.3 (0.56) 301.9(0.84) 300.6 (0.54) 301.2 (0.76) 297.3 (0.58) 301.7 (0.94) 303.6 (0.42)302.2 (0.40) 296.4 (0.40) 303.2 (0.77) 299.6 (0.76) 302.1 (0.33)Hardness min-max (kp)* 3.70 (2.4-5.9) 3.35 (3.0-3.9) 4.34 (3.8-4.8) 4.45(4.9-5.8) 3.57 (2.4-5.9) 3.72 (2.8-4.4) 3.13 (2.3-3.4) 4.92 (3.8-5.5)2.95 (2.8-3.2) 3.75 (3.1-4.6) 3.14 (2.1-4.0) 4.91 (4.6-5.4) Thicknessmin-max (mm) 4.15-4.41 4.01-4.12 4.01-4.19 4.01-4.04 Friability (%)Start/Middle/End 0.2/0.2/0.3 0.5/0.2/0.3 0.5/0.5//0.3 0.0/0.1/0.0Disintegration - Start (sec) 10 15 15 12 Disintegration - End (sec) 1014 16 14 Assay % label claim 95.5-95.6 98.6 99.3-100.1 97.2-99.3 RelatedSubstances (%) - RRT Unknown 0.79 ND ND 0.18 Unknown 0.89/0.90 ND/0.10ND/ND <0.10/0.11 Unknown 1.58/1.84 ND/ND ND/ND <0.10/ <0.10 Total 0.10<0.10 0.29 Time %Dissolved 10 Min 58 (1.9) 46 (2.6) 46 (3.1) 64 (2.5) 20Min 72 (1.1) 74 (15.2) 66 (1.1) 82 (0.9) 30 Min 79 (0.9) 85 (8.8) 77(1.2) 90 (1.2) 45 Min 84 (0.8) 89 (2.8) 86 (1.5) 93 (1.0) 60 Min 86(0.6) 92 (1.0) 91 (1.4) 95 (1.0) *--> Tested at Start, Middle and End ofcompression; ND --> not detected

Stability of Fluticasone ODTs batch 7 (0.75 mg), batch 8 (4.5) and batch9 (6 mg) is testes; these batches are packaged in 30 cc (30 tablets perbottle) HDPE bottles, with rayon coil and 0.5 g silica pouch dessicant(Sorb-it ½ g packet) included. All ODTs are stable at acceleratedconditions (40° C./75% RH) for a period of 6 months, as well as atlong-term stability conditions (25° C./60% RH) for a period of 9 months;all values measured at given time points (T=0, 1 month, 2 months, 3months, 6 months, 9 months) are within the acceptance criteria(disintegration: NMT 30 sec, assay: NLT 90.0% and NMT 110.0%, eachimpurity: NMT 0.5%, total impurity: NMT 1.5%). The physical properties,such as appearance, hardeness, friability, and disintegration time atall stability conditions are also comparable to the initial values ofthe corresponding Fluticasone ODTs.

While the invention has been described in connection with the specificembodiments herein, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to that the invention pertains and as may be applied to theessential features hereinbefore set forth and as follows in the scope ofthe appended claims.

What is claimed is:
 1. An orally disintegrating tablet comprising: a. atopically acting corticosteroid or pharmaceutically acceptable salt orester thereof, adsorbed onto a pharmaceutically acceptable carrier; andb. at least one disintegrant; wherein the topically actingcorticosteroid, or pharmaceutically acceptable salt or ester thereof, ispresent in an amount ranging from about 0.5 mg to about 10 mg, and thetopically acting corticosteroid, or pharmaceutically acceptable salt orester thereof, has a mean particle size of ranging from about 100 nm toabout 100 μm; and wherein the orally disintegrating tablet disintegrateswithin 60 seconds when tested using the USP <701>method fordisintegration time.
 2. The orally disintegrating tablet of claim 1,wherein the pharmaceutically acceptable carrier is selected from thegroup consisting of microcrystalline cellulose, silicifiedmicrocrystalline cellulose, pregelatinized starch, corn starch,colloidal silica, and amorphous magnesium aluminum silicate.
 3. Theorally disintegrating tablet of claim 2, wherein the pharmaceuticallyacceptable carrier is silicified microcrystalline cellulose.
 4. Theorally disintegrating tablet of claim 2, wherein said topically actingcorticosteroid, or pharmaceutically acceptable salt or ester thereof, isbudesonide, fluticasone, flunisolide, ciclesonide, mometasone,beclomethasone, or a pharmaceutically salt or ester thereof.
 5. Theorally disintegrating tablet of claim 4, wherein the topically actingcorticosteroid, or pharmaceutically acceptable salt or ester thereof, ispresent in an amount ranging from about 0.5 mg to about 3 mg.
 6. Theorally disintegrating tablet of claim 4, wherein said topically actingcorticosteroid is fluticasone or an ester thereof.
 7. The orallydisintegrating tablet of claim 4, wherein said topically actingcorticosteroid is fluticasone propionate.
 8. The orally disintegratingtablet of claim 1, wherein fluticasone propionate is present in anamount of about 3 mg in the orally disintegrating tablet.
 9. The orallydisintegrating tablet of claim 1, wherein fluticasone propionate ispresent in an amount of about 1.5 mg in the orally disintegratingtablet.
 10. The orally disintegrating tablet of claim 1, wherein thecorticosteroid has a mean particle size of ranging from about 100 nm toabout 10 μm.
 11. The orally disintegrating tablet of claim 1, whereinthe corticosteroid has a mean particle size ranging from about 100 nm toabout 4 μm.
 12. The orally disintegrating tablet of claim 1, wherein theat least one disintegrant is present in a rapidly dispersingmicrogranule, which comprises a sugar alcohol, or a saccharide, or amixture thereof in addition to the at least one disintegrant.
 13. Theorally disintegrating tablet of claim 12, wherein the sugar alcohol orsaccharide and the disintegrant are present in a ratio of sugar alcoholor saccharide to disintegrant of from 90:10 to 99:1.
 14. The orallydisintegrating tablet of claim 12, wherein the disintegrant is selectedfrom the group consisting of crospovidone, sodium starch glycolate,crosslinked carboxymethyl cellulose, and low-substitutedhydroxylpropylcellulose.
 15. The orally disintegrating tablet of claim12, wherein the sugar alcohol or saccharide is selected from the groupconsisting of sucralose, lactose, sucrose, maltose, mannitol, sorbitol,xylitol, maltitol, and mixtures thereof.
 16. The orally disintegratingtablet of claim 12, wherein the rapidly dispersing microgranule has amean particle size of less than about 300 μm, and the sugar alcoholand/or saccharide has an average particle size of less than about 30 μm.17. The orally disintegrating tablet of claim 1, wherein thepharmaceutically acceptable carrier is present at an amount of about 10%w/w based on the total weight of the orally disintegrating tablet. 18.The orally disintegrating tablet of claim 1, wherein the total weight ofthe tablet is in the range of from about 300 to about 900 mg.
 19. Anorally disintegrating tablet comprising: a. fluticasone propionateadsorbed onto microcrystalline cellulose, silicified microcrystallinecellulose, pregelatinized starch, corn starch, colloidal silica,amorphous magnesium aluminum silicate, or combinations thereof; and b.at least one disintegrant, wherein: the fluticasone propionate ispresent in an amount ranging from about 0.5 mg to about 6 mg, and thefluticasone propionate has a mean particle size ranging from about 100nm to about 10 μm; and wherein the orally disintegrating tabletdisintegrates within 30 seconds when tested using the USP<701>Disintegration test.
 20. The orally disintegrating tablet of claim19, wherein the microcrystalline cellulose, silicified microcrystallinecellulose, pregelatinized starch, corn starch, colloidal silica, oramorphous magnesium aluminum silicate, or a combination thereof, ispresent in an amount of about 10% w/w based on the total weight of theorally disintegrating tablet.
 21. The orally disintegrating tablet ofclaim 19, comprising silicified microcrystalline cellulose in an amountof about 10% w/w based on the total weight of the orally disintegrating.tablet.
 22. The orally disintegrating tablet of claim 19, whereinfluticasone propionate has a mean particle size of about 4 μm or less.23. The orally disintegrating tablet of claim 21, wherein thedisintegrant is selected from the group consisting of crospovidone,sodium starch glycolate, crosslinked carboxymethyl cellulose, andlow-substituted hydroxylpropylcellulose.
 24. The orally disintegratingtablet of claim 20, wherein the at least one disintegrant is present ina rapidly dispersing microgranule, which comprises a sugar alcohol, or asaccharide, or a mixture thereof in addition to the at least onedisintegrant.
 25. The orally disintegrating tablet of claim 24, whereinthe sugar alcohol or saccharide and the disintegrant are present in aratio of sugar alcohol or saccharide to disintegrant of from 90:10 to99:1.
 26. The orally disintegrating tablet of claim 24, wherein thesugar alcohol or saccharide is selected from the group consisting ofsucralose, lactose, sucrose, maltose, mannitol, sorbitol, xylitol,maltitol, and mixtures thereof.
 27. The orally disintegrating tablet ofclaim 24, wherein the rapidly dispersing microgranule has a meanparticle size of less than about 300 μm, and the sugar alcohol and/orsaccharide has an average particle size of less than about 30 μm. 28.The orally disintegrating tablet of claim 19, wherein the silicifiedmicrocrystalline cellulose is present in an amount of about 10% w/wbased on the total weight of the orally disintegrating tablet,fluticasone propionate is present in an amount ranging from about 1 mgto about 3 mg, and fluticasone propionate has a mean particle sizeranging from about 100 nm to about 4 μm.
 29. A method for treatingeosinophilic esophagitis in an individual in need thereof, comprisingadministering to the individual the orally disintegrating tablet ofclaim
 1. 30. A method of preparing the orally disintegrating tablet ofclaim 1, comprising the steps of: (a) micronizing the corticosteroid;(b) preparing preblend 1 by blending (i) a pharmaceutically acceptablecarrier, (ii) corticosteroid or pharmaceutically ester thereof, and(iii) glidant, under conditions suitable for the corticosteroid to beadsorbed onto the pharmaceutically acceptable carrier, wherein thepharmaceutically acceptable carrier is microcrystalline cellulose,silicified microcrystalline cellulose, pregelatinized starch, cornstarch, colloidal silica, and amorphous magnesium aluminum silicate; (c)preparing preblend 2 by blending filler, preblend 1 of step (b),disintegrant, and sweetener; (d) preparing a final compressible blend,by blending a disintegrant, lubricant, filler, and preblend 2 of step(c); (e) compressing the blend of step (d) to form a tablet.